Abstract

This report describes a four-day-old, full-term Connemara colt, presented for the
evaluation of a progressive inability to rise unassisted. A diagnosis of nutritional
muscular dystrophy was made based on muscular weakness, elevated muscle enzymes and
low vitamin E, selenium and glutathione peroxidase activity. The foal was treated
with intramuscular vitamin E-selenium and made a full recovery.

Keywords:

Case Report

Nutritional muscular dystrophy (NMD), also known as white muscle disease or nutritional
myodegeneration, is a non-inflammatory degenerative disease affecting both skeletal
and cardiac muscles, with animals presenting either in an acute or subacute form [6,13,16]. It is most commonly observed in regions in which there is selenium (Se)-deficient
soil, grains and forages [6,13]. The clinical presentation includes an acute and rapidly progressive syndrome leading
to death within hours to days, or a subacute form in which muscular weakness is the
most common presentation [16,13]. NMD has been reported in cattle, sheep and pigs, occurring less frequently in horses,
in various regions in the United States, Canada, the United Kingdom, New Zealand,
Australia and Europe [18]. It has also been reported to affect foals ranging in age from neonates to older
weanlings [13]. We report a case of diffuse muscular weakness in a four-day-old foal in which NMD
was diagnosed based on the clinical presentation and laboratory findings including
low serum vitamin E and Se concentrations. Although selenium toxicity has been reported
in horses (as well as cattle and sheep) in the Republic of Ireland [19], to the authors' knowledge this is the first report of NMD in a foal in the Republic
of Ireland.

Case Details

A four-day-old, full-term 45 kg Connemara colt presented to University College Dublin
(UCD) with a two day history of progressive inability to rise unassisted. Gestation
and parturition were reportedly uneventful, and although there was mild flexor contraction
of all four limbs, the foal could stand and nurse easily on its own. The mare was
maintained on a grass pasture with no supplements. Deworming and vaccination history
were unknown and there had been no dietary or management changes. The mare had one
previous healthy foal. At two days' of age, the foal was observed having trouble rising
on its own; the following day, the foal could not get up without assistance, appeared
to be weaker and passed tea-coloured urine. The foal was referred into UCD the following
day.

Clinical Findings

Upon presentation, the foal was bright, alert and standing. When recumbent, it needed
assistance to stand, but once up, could move around without assistance. The foal had
normal nursing behaviour and when suckling, swallowed normally. All joints and the
umbilicus palpated within normal limits, and there was moderate flexural contraction
of all four limbs involving primarily the distal interphalangeal joint, with the right
front the most severely affected. The flexural deformities did not appear severe enough
on their own to cause the foal's inability to rise without assistance. The foal was
observed to urinate frequently in normal quantities with no straining; the urine grossly
appeared to be normal. The mucous membranes were pink and moist with a capillary refill
time of less than two seconds, and temperature, pulse and respiration were all within
normal limits. Observing the colt's hindlimbs from the side, they appeared to be in
a 'C'-shaped configuration with a downward slope of the pelvis (Figure 1). The remainder of the physical examination, including a neurological examination,
was within normal limits. No signs of trauma were noted and no ectoparasites were
found.

Figure 1.A four-day-old full-term Connemara colt that presented to University College Dublin
with a two-day history of progressive inability to rise unassisted. Note the moderate flexural contraction of all four limbs involving primarily the
distal interphalangeal joint and the 'C'-shaped configuration of the hindlimbs and
downward slope of the pelvis.

Based on the physical and neurological examination, the primary problem appeared to
be generalised muscular weakness. Differentials at this time for muscular weakness
included systemic illness (sepsis, neonatal isoerythrolysis), neuromuscular abnormalities
(tick paralysis, botulism), musculoskeletal abnormalities (myopathies secondary to
inflammatory/infectious, traumatic, degenerative [inherited, metabolic, nutritional]
and ischaemic causes, incomplete ossification of the cuboidal bones), dysmaturity,
metabolic/electrolyte derangements (hyperkalaemia, hypokalaemia, hypocalcaemia) and
endocrine disorders (hypoadrenocorticism, hypothyroidism). Although the foal appeared
to be weak rather than ataxic, congenital disorders of the vertebrae/spinal cord and
trauma to the vertebrae/spinal cord including the pelvis could not be ruled out.

Blood was submitted for a complete blood count (CBC) including fibrinogen, serum biochemistry,
venous blood gas, immunoglobulin G (IgG) concentrations and aerobic and anaerobic bacterial culture. Radiographs taken of
the hocks and carpi revealed normal ossification, while radiographs of the distal
limbs showed no congenital abnormalities which might explain the presence of the flexural
deformities. Radiographs taken of the lumbosacral spine revealed no evidence of trauma.

The IgG concentration was 400 mg/dl (4 g/l) (reference range >800 mg/dl [>8 g/l]) indicating
partial failure of passive transfer. The blood culture yielded no growth after one
week of incubation. The CBC was unremarkable, while the serum biochemistry revealed
a profound hyponatraemia (118 mmol/l; reference range 132-146 mmol/l), hyperkalaemia
(4.52 mmol/l; reference range 2.7-3.5 mmol/l) and hypochloraemia (85 mmol/l; reference
range 98-104 mmol/l), and a severely elevated creatinine phosphokinase ([CPK] 2450
iu/l; reference range <70 iu/l) and aspartate aminotransferase ([AST] 4970 iu/l; reference
range 101-154 iu/l); the blood urea nitrogen (BUN) and creatinine concentrations were
within normal limits. The main differentials for foals with hyponatraemia, hyperkalaemia
and hypochloraemia include uroperitoneum due to rupture of part of the urinary tract
(most commonly bladder), renal disease and muscle degeneration (rhabdomyolysis). Adrenal
insufficiencies, as well as gastrointestinal (GI) diseases such as enterocolitis were also considered, but given both the lack of historical evidence and clinical
signs, GI diseases were considered unlikely to be involved. The main differential
for elevations in serum CPK and AST is a myopathy (inflammatory/infectious [sepsis, clostridial myositis], traumatic, degenerative [inherited, metabolic, nutritional], ischaemic). Causes
of inherited myopathies include polysaccharide storage myopathy and glycogen branching
enzyme deficiency while nutritional causes include NMD.

Ultrasonography of the abdomen including both kidneys demonstrated an intact bladder
with no free fluid. A free-catch urine sample was examined revealing a specific gravity
of 1.006, with no evidence of blood. Renal disease was considered unlikely since there
was no evidence of azotaemia, and the low urine specific gravity was considered to
be normal in a nursing foal. Although neonates can adequately concentrate their urine,
they typically have very dilute urine (1.001-1.006) due to their almost completely
liquid (i.e., milk) diet. Based on the above findings and the elevated serum muscle
enzymes, rhabdomyolysis was considered to be the cause of the electrolyte disturbances,
although adrenal insufficiency could not be completely ruled-out. Based on the signalment,
clinical, laboratory and radiographic findings infectious, traumatic, inherited and
ischaemic causes of myopathy in this foal were all considered unlikely with the primary
differential being NMD.

Treatment

An intravenous jugular catheter was placed and treatment initiated including 0.9%
sodium chloride and 5% dextrose (2.2 ml/kg/hr, IV), ceftiofur HCl (Excenel, Pfizer
Animal Health) (2.2 mg/kg, IV, q 12 h) and omeprazole (Gastroguard, Merial)(4 mg/kg,
PO, q 24 h). A dextrose-containing solution was chosen in an attempt to reduce serum
potassium concentrations by driving potassium into the cells. Despite evidence of
partial failure of passive transfer, the owner declined treatment with intravenous
plasma based on financial costs, the lack of evidence of sepsis and that fact that
the foal was on systemic antibiotics. The foal was assisted to stand every two hours
and nursing, urination and defecation were monitored. The following day, the foal
was stronger, but still could not rise unassisted. A repeat CBC and serum biochemistry
revealed the foal still to be hyponatraemic (123 mmol/l), hyperkalaemic (4.33 mmol/l)
and hypochloraemic (88 mmol/l) with elevated serum muscle enzymes (CPK 648 iu/l; AST
3485 iu/l). Results from urine collected prior to fluid therapy and submitted for
sediment analysis and fractional excretion of electrolytes were within normal limits.
A repeat venous blood gas revealed a mild metabolic acidosis (pH 7.3, reference range
7.35-7.45; HCO3- 20.8 mEq/l, reference range 22-26 mEq/l), possibly due to lactic acid release from
muscle and alterations in strong ions (i.e., hyponatraemic acidosis).

To investigate for nutritional causes (i.e., NMD), blood was submitted from the mare
and foal for measurement of vitamin E (two samples taken at different times of the
day), Se and glutathione peroxidase (GPx). The owner declined a muscle biopsy due
to financial restrictions. Baseline cortisol was also measured from blood samples
taken at two different times to assess the adrenal function. The foal was then treated
with a vitamin E-Se combination (Vitesel, Norbrook Laboratories Limited) (2.5 mg Se
[2.5 mg/45 kg], IM, once, divided into two deep injections given in the semimembranosus
muscles). As the foal was tolerating the fluid load, intravenous fluid therapy was
continued at the same rate but changed to a solution containing a total of 234 mEq/L
of sodium with bicarbonate and dextrose (NaHCO3, 90 mEq added to 10% dextrose in 0.9% saline, 1 L) to help drive potassium intracellularly.
Carprofen (Rimadyl, Pfizer Health Corp) (0.7 mg/kg, IV, once) was also given to address
any inflammation and pain associated with muscle degeneration and with the flexural
contractions. The foal also received physical therapy on the contracted tendons two
to three times per day.

By the third day the foal was brighter, able to get up unassisted, moved around the
stall more freely and appeared less contracted with less sloping of the pelvis. A
repeat venous blood gas, CBC and serum biochemistry including the sodium (135 mmol/l),
potassium (3.86 mmol/l) and chloride (97 mmol/l) concentrations were all within normal
limits. The serum CPK (493 iu/l) and AST (1340 iu/l) concentrations had both decreased
significantly, indicating both resolution and lack of ongoing muscle damage. The foal's
cortisol concentrations were within normal limits, while the GPx (10.1 u/ml PCV; reference
range 30-150 u/ml PCV), blood Se (0.5 μmol/l; reference range 0.75-3.0 μmol/l) and
serum vitamin E (2.1 μmol/l from first sample, 1.4 μmol/l from the second sample;
reference range 3.0-20.0 μmol/l) concentrations were all low, supporting the diagnosis
of NMD; the mare's GPx (38 u/ml PCV), blood Se (1.94 μmol/l) and serum vitamin E (5
μmol/l) concentrations were all within normal limits. Based on the normal electrolyte
concentrations and decreasing muscle enzymes, intravenous fluids were discontinued.
The following day, the foal remained bright and alert and able to get up on its own,
with all serum electrolyte concentrations within normal limits. and both the serum
CPK (280 iu/l) and AST (1026 iu/l) concentrations further decreased. The foal was
administered a second treatment of vitamin E-Se (2.5 mg Se, IM, once) and carprofen
(0.7 mg/kg, IV, once) and discharged on the sixth day of hospitalisation. In order
to minimise muscle damage secondary to exertion, and to allow for continued muscle
healing, it was instructed to keep the mare and foal stall-restricted for at least
one week, followed by turn-out into a small paddock. It was recommended to treat the
foal with vitamin E-Se at 10 days and six to eight weeks of age and also to supplement
the animal with oral vitamin E since the intramuscular formulation contains very little.

Although the mare's GPx, blood Se and serum vitamin E concentrations were all within
normal limits, it was suspected that the mare had been deficient at one point during
gestation since a foal's vitamin E and Se status are directly affected by the mare's
status. Thus, it was recommended that vitamin E and Se be measured for the rest of
the herd, especially for any remaining pregnant mares, and to supplement any of the
deficient pregnant mares prior to parturition along with treating their foals with
vitamin E-Se when born, and again at two and six weeks of age. Since Se toxicity can
occur, it was recommended that the dose of Se not exceed 200 μg/kg in foals.

Fifteen months following discharge the colt was reported doing well, with no problems
with the remainder of the herd.

Discussion

NMD is a non-inflammatory degenerative disease affecting both skeletal and cardiac
muscles, with animals presenting either in an acute or subacute form [6,13,16]. Although Se toxicity has been reported in horses (as well as cattle and sheep) in
the Republic of Ireland and Se deficiency has been reported to be widespread in cattle
and sheep in most of the counties in the Republic of Ireland [19], to the authors' knowledge this is the first report of NMD in a horse in the Republic
of Ireland. The disease occurs in regions with Se-deficient soils, resulting in the
production of Se-deficient grains and forages [6,13,16]. In the equine and other species, NMD is also associated with vitamin E deficiency
[13]. Vitamin E and Se act synergistically to prevent peroxidative damage of lipid-containing
membranes, with vitamin E inactivating oxygen-free radicals while Se is a component
of the enzyme glutathione peroxidase which acts to destroy already formed oxygen-free
radicals [3,13].

Typically, foals with subacute NMD are bright and alert with profound muscular weakness
as seen with the foal described here [6,13,16]. Foals that have myocardial, as well as skeletal muscle degeneration, may present
with an arrhythmia, tachycardia and profound weakness that may result in sudden death
[6]. In addition to general muscular weakness, animals may present with dysphagia resulting
in secondary complications such as aspiration pneumonia and failure of passive transfer
[6,16]. The foal described here did have partial failure of passive transfer, but did not
have clinical evidence of dysphagia nor aspiration pneumonia, although endoscopy and
thoracic radiographs were not performed. Full and partial failure of passive transfer
may occur due to inadequate colostral immunoglobulin concentration (decreased production,
premature lactation), inadequate colostral intake (failure to suckle, dysphagia) and
poor gut absorption. Although the foal had been observed by the owners to stand and
nurse normally following parturition, it is possible that the foal did not take in
adequate amounts of colostrum before gut closure due to an inability to rise and nurse
as frequently as a normal foal would. Interestingly, it has been demonstrated that
mares supplemented with a synthetic form of vitamin E resulted in an increased passive
transfer of immunoglobulins to foals, likely as a result of increased concentrations
of immunoglobulins in their colostrum [9,10]. Therefore, mares with low vitamin E may have decreased concentrations of colostral
immunoglobulins contributing to failure of passive transfer to the foal.

The diagnosis of NMD is based on a combination of typical clinical signs, elevated
muscle enzymes, decreased blood Se and/or GPx activity and response to treatment with
vitamin E-Se [6,16]. Muscle biopsies may be useful in defining characteristic histological lesions such
as hyaline degeneration, lysis and fragmentation of muscle fibres [13], although alone they are not diagnostic. Serum CK and AST values are typically elevated
in foals with NMD [6,13,16,17], as found in the current case. CK is the most muscle-specific enzyme and indicates
active muscle damage as it increases quickly (four to six hours) following muscle
damage and has a relatively short half-life (six hours), returning to normal within
48 hours after muscle damage has stopped [7]. In most foals, recumbency will not result in CK activity greater than 1000 u/L,
while CK activity greater than 5000 u/L typically indicates myodegeneration [13]. Although not performed in the present case due to financial restrictions, serum
cardiac muscle isoenzymes (CK, LDH) and serum troponin I can be measured to evaluate
for myocardial damage. Rhabdomyolysis often contributes to the development of hyponatraemia,
hyperkalaemia and hypochloraemia. As the musculature makes up approximately 55% of
the total body mass [6] and is a major intracellular reservoir for potassium and phosphorus, disruption of
the muscle cell wall allows a large efflux of these intracellular electrolytes and
an influx of water, sodium and chloride into the muscle tissue resulting in the above
described electrolyte disturbances [2,17]. These electrolyte changes typically coincide with the onset of clinical signs and
increase in CK activity in foals with acute rhabdomyolysis [17]. However, because of the development of myoglobinuria as a result of muscle breakdown,
foals with acute rhabdomyolysis may develop secondary acute renal failure as a result
of pigment nephropathy. Thus, foals with acute rhabdomyolysis need to have their renal
function closely investigated and monitored during the duration of the disease process.

The activity of GPx, a Se-containing enzyme, strongly correlates with blood Se concentrations
[20], since Se is incorporated into red blood cells (RBC) as GPx during erythropoiesis
[21]. Thus, GPx activity is a good indicator of the animal's Se status weeks to months
prior to the sample collection [12] while blood Se concentrations assess the animal's current Se status [16,13]. Foals deficient in Se, such as the foal described in this report, will have low
GPx activity when RBCs that had matured in a period of adequate Se are replaced with
RBCs that had matured during a period of Se deficiency [16]. However, neither a decreased blood Se nor GPx activity alone is sufficient for the
diagnosis of NMD, since animals raised in Se-deficient areas with no clinical signs
of NMD may have decreased blood Se and/or GPx activity [6,12,16,20].

The main treatments for foals with NMD include intramuscular injections of vitamin
E and Se products, exercise restriction and supportive care [6,13,16]. Since the injections can cause transient muscle pain, it is recommended to divide
the dose and give into deep muscles at two separate sites [6,14]. The amount of vitamin E in currently available combined vitamin E-Se products is
minimal, so if NMD is believed to be due to vitamin E deficiency, then supplementation
with additional vitamin E is recommended. Interestingly, although there appears to
be a joint role for vitamin E and Se in the prevention of NMD, Se given alone has
been shown to be effective in treating and preventing the disease [6]. Mildly affected foals, such as in this report, improve rapidly following Se injections
even though there is a significant delay before improvements in GPx activity can be
documented [14]. Since acute Se toxicity can occur, it is recommended not exceed 200 μg/kg in foals
[24]. Clinical signs of acute toxicity include depression, ataxia, muscle weakness, blindness,
diarrhoea, dyspnoea and a garlic odour to the breath [6,22,23].

Hyperkalaemia may be the most life-threatening electrolyte abnormality in foals with
NMD due to the possibility of cardiac arrhythmias. Typical treatments for hyperkalaemia
include the use of glucose, sodium bicarbonate and insulin in an attempt to drive
potassium from the extracellular to the intracellular fluid compartments [11]. With the current foal, we chose to initially use glucose in a potassium-free fluid,
followed by the addition of sodium bicarbonate. This was eventually successful, likely
because the muscle damage was only moderate which resulted in the maintenance of enough
intact muscle cells into which potassium could be driven [17]. Interestingly, foals with severe rhabdomyolysis often do not respond to the typical
treatments aimed at driving potassium intracellularly, as a result of the severity
of the muscle damage and major loss of the intracellular fluid compartments [17]. Thus, in the face of severe muscle damage it has been hypothesized that it may be
more efficacious to direct treatment towards enhanced potassium excretion through
the renal or GI system [17]. Mineralocorticoids, which act on the renal distal tubules and collecting ducts,
and/or diuretics such as furosemide can be used to increase renal potassium loss [4,8,17] while polystyrene sulfate, a cation exchange resin, increases faecal potassium loss
when given orally or rectally [4,11,17].

If dysphagic, it is recommended to muzzle the foal and support it nutritionally using
a nasogastric tube in order to prevent aspiration pneumonia. Because the foal in the
present report did not exhibit any clinical signs of dysphagia, it was decided to
allow the foal to continue to nurse from the mare. Interestingly, a previous report
found that three out of four foals diagnosed with NMD developed clinical evidence
of bronchopneumonia despite nasogastric feeding [17] while another report found that 24% of foals with NMD had a post-mortem diagnosis
of aspiration pneumonia [16]. It is therefore recommended to maintain foals with NMD on broad-spectrum antibiotics,
such as a third generation cephalosporin used in the current case, whether or not
the foal is maintained with nasogastric feeding [16,17].

Because equine neonates should gain 0.5-1 kg per day, the foal was weighed before
and every day following the initiation of drug and fluid therapy so as to adjust doses
accordingly, and to monitor hydration and adequate caloric intake. Interestingly,
large weight gains have been reported in foals 24 hours following the onset of acute
rhabdomyolysis [17], with the mechanism hypothesised to be a combination of activation of the renin-angiotensin
system and aldosterone release in response to hyperkalaemia and a large shift of water
into damaged muscle [2,17]. This was not noted in the present case, likely because the degree of muscle damage
and hyperkalaemia were only moderate.

The prognosis for foals with NMD is guarded, but decreasing CK activity found with
serial sampling, such as in the current case, has been associated with a good prognosis
[16]. Poor prognostic indicators include clinical signs associated with the acute form
of the disease, the inability of the foal to support its own body weight, severe myoglobinuria
and cardiac muscle involvement [6]. The acute form of the disease has a much poorer prognosis for survival than the
subacute form, with mortality rates of up to 95% while mortality rates for the subacute
disease range between 30-45% [5].

The last trimester of pregnancy is the most important time to monitor the vitamin
E-Se status of the mare and to supplement if needed [16]. Supplementing the mares in the prepartum period is an extremely efficient way to
protect the foals from Se deficiency, since the neonates' Se status depends largely
on the status of the mare during pregnancy [14]. When supplementing the mare with Se during gestation, various recommendations have
been made including 1 mg/horse/day [15], 4.4 mg/horse/week [15] or 6 mg/horse/week [1]. Treating foals at birth prophylactically with intramuscular Se does not prevent
NMD acquired in utero [13], but is recommended in foals from un-supplemented mares in vitamin E-Se deficient
regions whose vitamin E-Se status is unknown. Recommended protocols include 2.5 mg
Se/45 kg once, repeated two and six weeks later [6]. The Se status of the soil, forage and grain should also be investigated. It has
been reported that forage, grain and soil Se levels of <0.1 ppm suggest deficiency
[6].

In conclusion, NMD should be included as a differential in any foal that presents
with generalised muscular weakness. Confirmation of the disease is made based on the
typical clinical signs, elevations in CK and AST, evaluation of whole blood Se, vitamin
E and GPx activity and rapid response to vitamin E-Se therapy. Herd surveillance programs
with Se supplementation as required are the best ways to minimise the incidence of
the disease.